Prostate cancer (PC) is the most common tumor in men in western countries, and the second cause of cancer-related death among them. Almost 80% of cases are diagnosed as localized disease, and radiation or surgery can be curative. However, despite current treatment options, there is still a relapse rate of 30-60%.
Applicant has designed and synthesized of novel nonsteroid and steroid-mimetic compounds that cause down-regulation of the androgen receptor (AR), both full length and splice variant, induce apoptosis and inhibit proliferation of both androgen sensitive and castration resistant human prostate cancer cells. These steroid compounds and nonsteroid compounds may be agents for the prevention and/or treatment of all forms of prostate cancer and all other diseases that depend on functional AR.
AR is a well established target for therapeutic intervention in prostate cancer.
Other androgen receptor associated conditions that may be prevented and/or treated in the present invention include bladder cancer, pancreatic cancer, hepatocellular carcinoma, benign prostatic hyperplasia (BPH) and Kennedy's disease.
Androgen and androgen receptor (AR) play crucial role in the development and advancement of PC. As a consequence, for locally advanced or metastatic disease, hormonal treatment with androgen deprivation therapy, which blocks the production (CYP17 inhibitors: Abiraterone; 1) and/or activity of androgen (anti-androgens, Bicalutamide; 2), is a standard approach for the majority of patients (Chart 1), but most cases the duration of response is limited to 12-24 months, and the disease will become castration-resistant (CRPC) with no treatment options. Approximately 85% of CRPC patients succumb within 5 years and docetaxel (3) is currently the only treatment shown to provide even minimal survival benefit.
In castration-resistant environment aberrant AR reactivation is implicated through numerous mechanisms which leads to over expression of mutated AR, AR amplification and local androgen synthesis.5-Recently, multiple alternative spliced AR isoforms (AR-Vs) have been identified in CRPC. Unlike full-length AR (fAR) these AR-Vs are lack of the hormone-binding domain and also their activities are independent of hormone. The AR-Vs are expressed at higher level in various tumors and are three to five times more potent than f-AR in transactivating activity. Patients expressing constitutively active AR-Vs will in the long-term probably not benefit from antiandrogen and therapies aiming to reduce androgen synthesis. In fact, ‘not all CRPC patients do however respond to novel antiandrogen (MDV3100; 4) and CYP17 inhibitors (1), and even those who do subsequently relapse within a few months’. Based on above findings it is envisioned that effective treatment of CRPC patients will require new drugs that can modulate all forms of AR such as AR down-regulating (ARD) agents (ARDAs). The substantial anti-PC efficacy of Phase II clinical candidate ‘Galetereone’ (VN/124-1, 5, Chart 1 below) in comparison to abiraterone is by virtue of its multi target mechanism of action (CYP-17 inhibition, antiandrogen and ARD activity). (http://clinicaltrials.gov/ct2/show/NCT01709734).
For the development of ARD agents Applicant recently systematically explored the structure of 5 (VN/124-1). In which chemical functions at C17, C16 and C3 of Galeterone modified while androstene scaffold unaltered. The C17 bezimidazole (Bzlm) ring in Galeterone is essential to block catalytic 17α-hydroxylation of pregnenolone and progesterone mediated by CYP17 enzyme to obtain bio-precursors of androgen biosynthesis. Where 3β-OH group forms single direct hydrogen bond between inhibitor and polar amino acid residue of CYP17 enzyme. Similarly 3β-OH or 3-keto group of natural and synthetic hormones are identical of the interactions that are conserved in the androgen, estrogen, glucocorticoid, mineralocorticoid and progesterone receptors. Therefore, H-bonding interaction of 3β-OH and keto group of synthetic and natural hormones are critical for ligand recognition by CYP17 and hormone receptors. The 3β-OH group in galeterone is responsible for potent CYP17 and antiandrogen activity. This is further supported by loss of antiandrogen and CYP17 inhibitory activity of galeterone on modification of its C3 substitution with imidazole carabamate (VNPT55 (6)) and pyridine carboxylate (VNPT178 (7)) group. This modifications also enhanced ARD by 8.25-fold against fAR, 4-fold against AR-Vs and 4-fold increase in anti-PC activity. Applicant has successfully discovered and reported first rather selective (Chart 2) AR down-regulating agents (both fAR and AR-Vs).
